Adjunctive electrophysical therapies used in addition to land-based exercise therapy for osteoarthritis of the hip or knee: A systematic review and meta-analysis

Objectives To review evidence for effectiveness of electrophysical therapies (EPTs), used adjunctively with land-based exercise therapy, for hip or knee osteoarthritis (OA), compared with 1) placebo EPTs delivered with land-based exercise therapy or 2) land-based exercise therapy only. Methods Six databases were searched up to October 2023 for randomised controlled trials (RCTs)/quasi-RCTs comparing adjunctive EPTs alongside land-based exercise therapy versus 1) placebo EPTs alongside land-based exercise, or 2) land-based exercise in hip or knee OA. Outcomes included pain, function, quality of life, global assessment and adverse events. Risk of bias and overall certainty of evidence were assessed. We back-translated significant Standardised Mean Differences (SMDs) to common scales: 2 points/15% on a 0–10 Numerical Pain Rating Scale and 6 points/15% on the WOMAC physical function subscale. Results Forty studies (2831 patients) evaluated nine different EPTs for knee OA. Medium-term effects (up to 6 months) were evaluated in seven trials, and one evaluated long-term effects (>6 months). Adverse events were reported in one trial. Adjunctive laser therapy may confer short-term effects on pain (SMD -0.68, 95%CI -1.03 to −0.34; mean difference (MD) 1.18 points (95% CI -1.78 to −0.59) and physical function (SMD -0.60, 95%CI -0.88 to −0.34; MD 12.95 (95%CI -20.05 to −5.86)) compared to placebo EPTs, based on very low-certainty evidence. No other EPTs (TENS, interferential, heat, shockwave, shortwave, ultrasound, EMG biofeedback, NMES) showed clinically significant effects compared to placebo/exercise, or exercise only. Conclusions Very low-certainty evidence supports laser therapy used adjunctively with exercise for short-term improvement in pain and function. No other EPTs demonstrated clinically meaningful effects.


Introduction
Non-pharmacological interventions including exercise, education and weight management are recommended core treatments for osteoarthritis (OA) across numerous clinical guidelines [1][2][3][4].Other conservative non-pharmacological therapies combined with exercise therapy include electrophysical therapies (EPTs), which deliver thermal, mechanical, light, sound or electrical energy to provide physiological changes and confer therapeutic effects.EPTs are largely not recommended in international OA clinical guidelines due to low quality evidence or implausible biological mechanisms [1][2][3][4], although thermal agents and ultrasound were conditionally recommended in one guideline [2].
A Cochrane review of 62 trials (6508 participants) evaluating the effects of adjunctive non-pharmacological therapies used with landbased exercise therapy found, based on moderate-to low-certainty evidence, no difference in pain, physical function or quality of life (QoL) between adjunctive EPTs compared to their placebo equivalent/exercise, or exercise only [5].When various EPTs, such as therapeutic ultrasound (US), laser therapy, transcutaneous electrical nerve stimulation (TENS), shortwave/pulsed electromagnetic energy (PEME), interferential therapy (IFT), electromyographic (EMG) biofeedback and shockwave therapy were combined together into one adjunctive therapy EPT subgroup for analysis, we found no important effects across outcomes in either comparison (adjunctive placebo therapy/exercise or exercise) [5].However, as the effects of specific EPTs were not investigated, further exploration of their individual effects when used as adjuncts to land-based exercise for hip or knee OA was warranted.
This review aimed to compare the effects of different types of EPTs, used adjunctively with land-based exercise therapy, for people with hip or OA, compared with 1) a placebo EPTs delivered with land-based exercise therapy or 2) land-based exercise therapy only.

Method
This review protocol was prospectively registered with PROSPERO (CRD-42022380247) and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [6].

Search strategy and screening
We updated searches completed for the Cochrane review (up to June 2021), by searching the following databases, retaining all search terms from the original review, up to 26 Oct 2023: Medline, Cochrane Central Register of Controlled Trials, PsycINFO, EMBASE, CINAHL Plus and the Physiotherapy Evidence Database (https://pedro.org.au/), with no language restrictions (supplemental file 1).Two review authors (HPF and SA) independently screened titles and abstracts of retrieved citations from the updated searches against the review eligibility criteria, following removal of duplicates.Full-texts were retrieved, when eligibility could not be determined from the title or abstract.Screening was undertaken using Covidence (Veritas Health Innovation, Melbourne, Australia).

Eligibility criteria
Our inclusion criteria were Randomised Controlled Trials (RCTs) or quasi-RCTs, adults aged !18 years, with clinical or radiographic diagnosis of hip or knee OA as defined in the trials.Where trials included mixed populations, at least 75% of participants must have had knee and/ or hip OA [7].The intervention was adjunctive EPTs, which could include, but were not limited to thermal modalities, therapeutic US, laser therapy, TENS, pulsed electromagnetic energy (PEME)/shortwave, interferential therapy (IFT), electromyographic (EMG) biofeedback, phonophoresis, iontophoresis or shockwave therapy, delivered with land-based exercise.The comparator intervention was land-based exercise therapy, which could include supervised or home-based exercise regimens for knee or hip OA, delivered with a placebo adjunctive EPT or on its own.The exercise therapy in both groups must have been identical so that the only difference between the groups was the addition of the EPT.Comparators could include either 1) the same placebo adjunctive EPT delivered with identical exercise therapy, or 2) identical exercise therapy, with no adjunctive EPT.Abstracts, protocols, conference proceedings and unpublished data were excluded.

Outcomes
We included studies assessing pain and physical function as the primary outcomes [8].Secondary outcomes included participant-reported global assessment, QoL, radiographic joint structure changes and adverse events.
All outcomes were assessed immediately post-intervention (shortterm).If intervention duration differed between exercise therapy and adjunctive EPT, the EPT time-point was used.We also assessed mediumterm (<six months) and long-term outcomes (>six months postintervention).

Data extraction
Data extraction for the Cochrane review was undertaken by two independent review authors (HPF/RG), and by HPF and JC for additional studies identified up to 2023.We extracted follow-up data, with related standard deviations (SDs) for continuous outcomes.Missing SDs were calculated using provided 95% confidence intervals (CIs).If further data were required, study authors were contacted a maximum of three times via email.We used graph digitisation software (https://automeris.io/WebPlotDigitizer/) to extrapolate means and SDs by digitalising data points on graphs in two studies [9,11].

Risk of bias assessment
Risk of bias (RoB) of the six new studies was assessed by three independent review authors (HPF, SA and JC) using the Cochrane RoB V1 tool, while retaining original RoB judgements from the Cochrane review for this review [5].We graded each source of bias as low, high or unclear risk and discussed RoB judgements to reach consensus.

Data synthesis and analysis
Cochrane's Review Manager (version 5.4) was used for data analysis, using a random-effects model, assuming clinical heterogeneity.Dichotomous outcomes (e.g.adverse events) were reported as risk ratios (RRs) with 95% CIs.Continuous outcomes (pain, function, QoL), were calculated using Standardised Mean Differences (SMDs) and 95% CIs, using post-intervention values and if not available, we used change scores [10].
Where pooled effect estimates of continuous outcomes were statistically significant, to enhance interpretability of measures of treatment effect, we back-translated SMDs to a common scale by multiplying the SMD by a typical among-person standard deviation (SD) [13].This was obtained from a control group SD from the most representative trial with the highest weight in the meta-analysis and least susceptibility to bias.For pain measures, we back-translated to an 11-point Numerical Pain Rating Scales (NPRS), assuming that visual analogue scales (VAS) and NPRS were comparable.For physical function, we back-translated to the Likert version (0-68) WOMAC physical function subscale [14].We assumed a minimal clinically important difference (MCID), including mean difference and 95% CIs of 2 points [15] or relative (percentage) difference of 15% [16] on a 0-10 NPRS, 6 points on the 0-68 WOMAC Likert physical function subscale [17], and percentage change of 15%.Further detail on data synthesis and analysis is available in the Cochrane review [5].
Due to addition of new trials in this review, the Grading of Recommendations, Development and Evaluation (GRADE) of the overall certainty of the evidence in each pooled analysis from the Cochrane review was reassessed by two independent review authors (HPF and SA or JC), using GRADEPro software.Domains assessed included RoB, consistency of effect, precision of effect estimates, directness of the evidence and publication bias [18].Certainty of cumulative evidence started at 'high' and was downgraded for each domain not judged as low risk (Supplemental file 2).

Study selection
The original Cochrane review search conducted up to 10 June 2021 identified 181 articles, which were retained for full-text screening, from which 62 studies were included.For this review, 36 studies, which investigated adjunctive EPTs were retained, and searches (using the original search strategy (Supplementary file 1) rerun across the six databases in November 2022 and updated in October 2023.Following screening of 3516 titles and abstracts by two review authors (HPF and SA), 37 were retained for full-text screening and six studies were included in this review [11,[19][20][21][22][23], along with the original 36 EPT trials from the Cochrane review [5].Of these newly included studies, one reported different outcomes [21] from a trial previously included in the Cochrane review [24].Therefore, 41 papers from 40 trials (2831 participants) were included in this review.The PRISMA flow diagram is shown in Fig. 1.

Meta-analysis
As data could not be retrieved from one study [47], 39 studies were included in the meta-analysis.All studies reported end-of-treatment scores or provided relevant data on request [33], except for one, which reported change scores only [52].
One trial evaluated long-term effects of laser therapy, with no statistically significant difference between the groups based on a 0-100 VAS (MD 4.88, 95% CI -11.07 to 20.83) (Supplemental file 4).
Six studies (nine comparisons) evaluated medium-term effects on physical function.Overall pooled estimate (SMD -0.13, 95% CI -0.31 to 0.05) was not statistically significant, with negligible heterogeneity (I 2 ¼ 0%).Pooled results of subgroups of five different EPTs showed no statistically significant difference between-group differences (Supplemental file 5).
One trial evaluated long-term effects of laser therapy, with no statistically significant difference between the groups based on a 0-100 KOOS disability subscale (MD 6.28, 95% CI -6.35 to 18.91).(Supplemental file 5).

Global rating of change
One trial evaluated global assessment post-intervention [23].A total of 81% improved in the laser therapy group compared to 87% in the  placebo group, resulting in a non-significant risk ratio (RR) of 0.92 (95% CI 0.73 to 1.17) (Supplemental file 7).

Adjunctive EPTs plus exercise therapy versus exercise therapy only pain
For short-term effects, the overall effect estimate of SMD -0.08 (95% CI -0.42 to 0.26) was not statistically significant, based on 21 trials (25 comparisons).Heterogeneity was considerable (I 2 ¼ 86%).No subgroups (laser, US, TENS, shortwave, shockwave, NMES, heat and EMG biofeedback) showed a statistically significant difference between the two groups (Fig. 4).One trial evaluated medium-term effects of laser therapy, with no statistically significant difference between the groups based on a 0-10 VAS (MD -0.50, 95% CI -1.28 to 0.28) (Supplemental file 9).

Physical function
The overall effect estimate for physical function was a SMD of À0.17   Heterogeneity was considerable (I 2 ¼ 78%), which was not statistically significant.
None of the subgroups of EMG biofeedback, heat therapy, laser, IFT, shockwave or shortwave showed statistically significant differences between the two groups (Fig. 5).
Two trials evaluated medium-term effects of laser therapy, with no statistically significant difference between the groups (SMD 0.23, 95% CI -0.68 to 1.15) (Supplemental file 9).
One trial of laser therapy evaluated medium-term effects on QoL, resulting in a MD -6.20 (95% CI -14.04 to 1.64), based on a 0-100 SF-36 mental health scale, which was not statistically significant (Supplemental file 9).

Adverse events
No trials in the EPT and exercise versus exercise only comparison reported on adverse events or withdrawals due to adverse effects.

Other secondary outcomes
Radiographic joint structure changes were not reported in any of the 40 trials.

Risk of bias and certainty of evidence
A summary of RoB judgements across domains associated with selection performance, detection attrition and reporting bias is shown in Fig. 6.For selection bias, 43% (17/40) trials were rated as low risk, based on random sequence generation, and 40% (16/40) were low risk based on allocation concealment.Just 35% (14/40) were deemed to be at low risk of performance bias, based on blinding of participants and personnel.Detection bias was assessed based on reporting of self-reported outcomes, with 30% (12/40) at low risk of bias, and 60% (24/40) rated as low risk of detection bias based on assessment of objective outcomes.A total of 60% (24/40) was rated as low risk of attrition bias, and 30% (12/40) were at low risk of reporting bias.
Using the GRADE approach to assess certainty of evidence for all EPTs combined and EPT subgroups, certainty of evidence ranged from 'moderate' to 'very low'.Publication bias could only be assessed for all EPTs and laser therapy, as 10 or more trials were included.Details of the GRADE assessment are available in Table 2 and funnel plots are in Supplemental file 10.

Discussion
This systematic review synthesised the evidence for different EPTs used adjunctively with exercise therapy for hip or knee OA.No trials investigated hip OA, so findings relate only to knee OA.Our original Cochrane review found, in subgroup analysis, statistically significant, but clinically unimportant, differences between adjunctive EPTs and corresponding placebo therapies in pain and function outcomes in the shortterm [5] and non-significant differences in QoL.Five additional trials added for this review [11,19,20,23,65] did not change results for overall effects.
However, this analysis aimed to primarily elucidate the effectiveness of different types of EPTs.Based on our first comparison against the  equivalent placebo therapy used with exercise therapy, only adjunctive laser therapy showed a statistically significant benefit in pain and physical function, which may be clinically important and based on verylow certainty of evidence, using the GRADE criteria.Therefore, these results should be cautiously interpreted.
For the second comparison of adjunctive EPTs and exercise therapy versus exercise therapy only, we found no statistically significant overall or subgroup effect across any EPTs.
Comparison with findings from other systematic reviews of EPTs, used adjunctively with exercise is limited, as their comparator intervention could have included a no-treatment control, or other nonexercise interventions [66][67][68][69][70].One review of NMES, based on six included trials, concluded that NEMS added to exercise demonstrated moderate evidence for improvements in muscle strength, but pain, function or QoL were not evaluated [71].Two recent reviews, which compared laser therapy as an adjunct to exercise, against exercise, both reported significant improvements in pain favouring laser therapy [72,73].They deemed these findings as clinically significant based on a mean difference (MD) of 13.41 (95% CI 5.46 to 21.37) on a VAS 0-100 pain scale [72], and a SMD of À0.55 (95% CI -0.88 to À0.22) [73].Back-translating SMDs, as we did in this review, increases the interpretability of pooled effect estimates into a more clinically meaningful result, but can be problematic as it potentially dichotomises treatments into 'worthwhile/not worthwhile'.A more nuanced approach that considers the complexity of the clinical encounter and patient wishes is suggested [74].Various MCIDs for pain severity have been used in knee OA reviews and guidelines, ranging from 10 to 19 on a VAS scale, resulting in conflicting treatment recommendations, rejecting treatments that may be effective, or accepting ineffective treatments [75].
At a physiological level, laser therapy is purported to modulate inflammatory processes and increase cellular proliferation [76,77] to improve pain and physical function in hip or knee OA.
In addition to physiological effects, which may translate into therapeutic effects, contextual factors, as potential contributors to treatment effects can include placebo effects, natural history and co-therapies, and have been shown to contribute a proportion of analgesic effects in nonpharmacological knee OA trials [78].Our inclusion only of studies with identical exercise in treatment and control groups may limit the role of contextual factors, although other factors, including patients' expectation, clinicians' behaviour and interaction [79], as contributors to contextual effects, cannot be accounted for in these trials.
Whilst evidence demonstrates the physiological effects of EPTs on body tissues [80], various reasons for lack of translation into clinical effects in trials include insufficient dosage [80], methodological issues including outcomes assessed, timing of outcome measurement and comparison groups used [81].The low quality of evidence of studies in this review is of concern, associated with the high proportion of trials demonstrating high or unclear risk of selection, performance, detection or attrition bias.The low sample sizes is also concerning.
Poor reporting of adverse events is also noteworthy, along with ambiguity around the nature of the events reported i.e., serious/nonserious, related/unrelated to the interventions, and whether there were resultant trial withdrawals.This is consistent with a systematic review, which identified inadequacies including adverse events assessment, reporting of withdrawals and details of adverse events in nonpharmacological trials [82].

Review strengths and limitations
Strengths include a comprehensive search strategy using six bibliographic databases, without English language restrictions.Risk of bias assessment and certainty of evidence using the Cochrane RoB and GRADE tools, was undertaken by two independent review authors.We included only studies where the exercise was identical in both control High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
and intervention arms, thereby evaluating the evidence for the additive effect of EPTs to exercise therapy.The high heterogeneity and low certainty of evidence is a limitation, along with variation in clinical parameters used, within EPT subgroups, creating clinical heterogeneity.Most trials assessed short-term outcomes only, with only six trials assessing medium-term (<6 months) effects, and one assessing long-term (>6 months) effects.

Implications for research and practice
No trials investigated hip OA, so results only apply to individuals with knee OA.Findings suggest a potential role for laser therapy alongside exercise therapy for knee OA for improving pain and physical function, however, results relate to short-term effects.Future RCTs should enhance methodological rigour by addressing various sources of bias.Robust, realistic sample size estimations should be undertaken a priori [83] and intervention fidelity should be evaluated.Trialists should review OARSI recommendations when designing and undertaking future clinical trials of EPTs [84].With recognition of OA as a chronic condition, longer-term follow-ups beyond six months are essential to provide meaningful results.Sufficient dosage to provide an optimal treatment effect should be a key consideration in future EPT trials.For example, greater treatment effects have been reported for knee OA trials of laser dosages aligned with the World Association of Laser Therapy (WALT) dosage recommendations [72].Future trials should follow the TIDieR [64] checklist to improve reporting of interventions.

Conclusion
Results suggest that across various EPTs used adjunctively with exercise therapy for knee OA, adjunctive laser therapy probably confers a clinical benefit in pain and physical function, when compared to placebo adjunctive laser, based on very-low certainty evidence.None of the other EPTs evaluated demonstrated clinically meaningful effects in pain and function over and above exercise therapy used either with a placebo EPT or on its own.Certainty of evidence was most commonly low or very low, and rarely moderate, across different comparisons.Results are predominantly based on short-term effects with few trials evaluating effects beyond six months.

Table 1
Characteristics of included studies.

Table 2
GRADE Summary of Findings tables.(a)Adjunctive Electrophysical Therapy and Exercise Therapy vs. Placebo Adjunctive Electrophysical Therapy and Exercise Therapy